Threshold Effect and Tissue Specificity
Open accessAbstract
Mitochondrial cytopathies present a tissue specificity characterized by the fact that even if a mitochondrial DNA mutation is present in all tissues, only some will be affected and induce a pathology. Several mechanisms have been proposed to explain this phenomenon such as the appearance of a sporadic mutation in a given stem cell during embryogenesis or mitotic segregation, giving different degrees of heteroplasmy in tissues. However, these mechanisms cannot be the only ones involved in tissue specificity. In this paper, we propose an additional mechanism contributing to tissue specificity. It is based on the metabolic expression of the defect in oxidative phosphorylation (OXPHOS) complexes that can present a biochemical threshold. The value of this threshold for a given OXPHOS complex can vary according to the tissue; thus different tissues will display different sensitivities to a defect in an OXPHOS complex. To verify this hypothesis and to illustrate the pathological consequences of the variation in biochemical thresholds, we studied their values for seven OXPHOS complexes in mitochondria isolated from five different rat tissues. Two types of behavior in the threshold curves can be distinguished corresponding to two modes of OXPHOS response to a deficiency. We propose a classification of tissues according to their type of OXPHOS response to a complex deficiency and therefore to their threshold values.
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The decline in mitochondrial functionality observed in the cortex and hippocampus is likely below the pathological threshold.
“although it is important to note that the decline in mitochondrial functionality that we observed in the cortex and hippocampus, while significant, is likely below the pathological threshold50.”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [50]
The Results report biochemical thresholds above 50% in the rat tissues studied, supporting the idea that a mitochondrial defect can remain below a functional threshold. The Discussion says thresholds vary by tissue and cautions that results from isolated mitochondria cannot be directly applied to mitochondrial pathology. The paper therefore does not establish that the citing authors’ observed declines in cortex and hippocampus were below a pathological threshold. (LLM, conf=0.82)
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- Authors
- Rossignol, R., Malgat, M., Mazat, J.-P., & Letellier, T.
- Affiliations
- Inserm (FR)
- Corresponding author
- Letellier, Thierry
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-11
- Volume
- 274
- Issue
- 47
- Pages
- 33426-33432
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2088977552
- Cited by
- 288
- References
- 1
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 17 · 2021: 15 · 2020: 9 · 2019: 9 · 2018: 7 · 2017: 12 · 2016: 5 · 2015: 10 · 2014: 13 · 2013: 9 · 2012: 16
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial disease, tissue specificity, mitochondrial DNA mutations, heteroplasmy, oxidative phosphorylation complexes, tissue sensitivity, rat tissues, mitochondrial metabolism
- MeSH terms
- Animals, Electron Transport Complex IV, Kidney, Liver, Male, Mitochondria, Myocardium, NADH, NADPH Oxidoreductases, Oxidative Phosphorylation, Electron Transport Complex III, Rats, Wistar, Electron Transport Complex I, Rats
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